Clumps of α-synuclein in neurons define Lewy body diseases, but tau tangles may add their own stamp to these disorders. Results from an imaging study, published September 19 in JAMA Neurology, suggest that tau pathology packs a cognitive wallop in people with dementia with Lewy bodies as well as those with Parkinson’s disease dementia. The researchers, led by Stephen Gomperts of Massachusetts General Hospital in Charlestown, also reported that in a few cases, tau pathology occurred in the absence of pathological accumulation of Aβ. The findings, some of which were presented at the International Dementia with Lewy Bodies Conference last year, support the idea that aggregated tau plays a role in the cognitive impairment that occurs in Lewy body diseases.
“This finding underscores the importance of tau accumulation in these disorders,” said Kejal Kantarci of the Mayo Clinic in Rochester, Minnesota. She added that the small size of the study makes replication crucial. Tanis Ferman of the Mayo Clinic in Jacksonville, Florida, agreed. “But this is an important first step to establishing the usefulness of tau imaging biomarkers in patients with Lewy body disease,” she added.
Lewy body diseases (LBDs) include Parkinson’s disease (PD), Parkinson’s disease with dementia (PDD), and dementia with Lewy bodies (DLB). They differ from each other by the order in which cognitive and parkinsonian (motor) symptoms arise (for a review, see Gomperts et al., 2016). While many people with PD only develop motor problems, those with PDD subsequently develop cognitive problems as well. In people with DLB, the symptom onset is reversed: cognitive troubles arise prior to parkinsonism.
Postmortem neuropathological studies have been telling researchers for some time that LBDs are anything but simple, since they do not fall into neat neuropathological categories. In addition to the flagship α-synuclein pathology, many people with LBDs also harbor AD-like neurofibrillary tangles and amyloid plaques. Because postmortem analyses offer but a snapshot of these complex co-pathologies after the fact, researchers now seek to use amyloid and tau imaging to track their interactions as disease progresses.
Last year at IDLBC, Gomperts presented preliminary findings from a small cross-sectional study in a cohort of people with LBDs. It measured Aβ accumulation via PiB retention, tau aggregation via AV-1451 uptake, and performance on the Cognitive Dementia Rating scale sum-of-boxes (CDR-SOB) and the Mini Mental State Examination (MMSE). Seven people had been diagnosed with DLB, eight with PDD, nine with PD, and 29 were cognitively normal controls (see Dec 2015 conference coverage). The main findings—based on single scans of Aβ and tau about two months apart—correlated high levels of tau tracer uptake in the inferior temporal gyrus (ITG) with waning cognition in people with DLB and PDD. Incidentally, the ITG is also the area where tau pathology starts to spread beyond the hippocampal formation in early AD. People with DLB had the most tau. AV-1451 uptake in some DLB patients rivaled that seen in people with AD.
The paper now elaborates on those preliminary findings. The researchers report that higher tau deposition in the ITG, and in the precuneus, correlated with cognitive impairment among the people with PDD and DLB. No such correlation emerged among healthy controls or PD patients. While the amount of tau detected—particularly in those with DLB—varied drastically among patients, its anatomic distribution in the brain was consistent, matching that in people with AD. This similarity suggests that the pathological processes driving tau accumulation in LBD may be similar to those that drive tau accumulation in AD, Gomperts told Alzforum.
Tracing Tau. People with DLB (left) accumulate more tau than PD patients who are cognitively impaired (middle) or have normal cognition (right). [Courtesy of Gomperts et al., JAMA Neurology 2016.]
However, in people with AD, the spread of tau into the cortex—a move that heralds cognitive impairment—reportedly occurs only after Aβ has accumulated (see Aug 2016 news and Mar 2016 news). Is this true in people with LBDs as well? Not entirely. Of 21 people with LBD, 17 (81 percent) had low amyloid burden. Despite having minimal Aβ, four of these people also had high tau tracer uptake in the ITG. This uncoupling of Aβ and tau, while only occurring in a small group of people, suggests that in LBDs, cortical tauopathy is possible without the extensive Aβ deposition characteristic of AD, Gomperts told Alzforum. He speculated that perhaps a synergistic relationship between α-synuclein and tau incited tauopathy in these patients, who were all cognitively impaired. Such a toxic relationship between the two proteins has been reported in animal models (see Jul 2013 news).
Johannes Attems of Newcastle University in England agreed with that assessment. He pointed out that the existence of moderate tau deposition in the absence of Aβ has been documented before, in people with primary age-related tauopathy (PART). However, PART happens without cognitive impairment, and Aβ is ultimately necessary to drive high levels of tau as well as cognitive impairment (i.e., AD). “Therefore, the most likely neuropathological correlate for dementia in the group with low amyloid burden and higher than normal tau burden in the inferior temporal gyrus in this study is α-synuclein pathology,” he commented.
Interestingly, the researchers also reported that in the DLB group, greater tau deposition in the ITG and precuneus associated with a shorter disease duration. This suggests that tau aggregation accelerates the progression of disease, said Gomperts. No correlation emerged between Aβ deposits and cognition across all groups.
The findings dovetailed with Ferman’s previous postmortem neuropathological analyses: DLB had progressed fastest in people with most tauopathy at autopsy. “[Gomperts’] study provides evidence that tau deposition can be measured in living patients with DLB and PD dementia, and that those with greater tau deposition tend to have greater cognitive impairment and greater dementia severity,” Ferman concluded.
To take full advantage of the benefits of live tau imaging, Gomperts plans to track the spread of tau pathology in people with LBDs over time.—Jessica Shugart
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